We have found that cocaine is a potent hepatotoxic agent in mice. The nature and extent of the liver damage produced by acute and chronic administration of cocaine will be examined in histological preparations and by measuring increases in serum transaminases. We will determine the effect of cocaine with other drugs, such as phenobarbital and ethanol. We will measure the effect of cocaine-induced liver damage on the rate of metabolism in vivo of cocaine and pentobarbital. In order to establish the mechanism by which cocaine damages cells we will study the metabolism of cocaine by the mixed function oxidase system, with the aim of defining the possible role of single oxygen and free radical intermediates such as cocaine nitroxide. The covalent binding of labeled cocaine metabolites to liver proteins will be investigated. The possible antigenicity of altered proteins released from the damaged liver will be studied in order to determine whether cocaine can produce an auto-immune disease. We have found that pretreatment with cocaine produces a long-lasting specific sensitization to the stimulant effects of cocaine in mice, as measured by the running response. We will attempt to relate this sensitization to alterations in cocaine metabolism by measuring the concentration of cocaine metabolites in the brains of mice after liver damage. These observations will be extended to other species of animals, including rats, guinea pigs, rabbits and monkeys. We will attempt to correlate the results of animal experiments with chronic pathological changes that have been encountered in the livers of human poly-drug-abusers.